Estrogen receptors (ERs), hormone-dependent transcription factors, are members of the nuclear receptor superfamily. The molecular design of hormone receptors is modular, containing individual domains designed for particular functions: ligand binding, DNA binding, activation of transcription and nuclear localization. These receptors are known to undergo conformational changes upon ligand binding which in turn, lead to their functions as transcription factors. These receptors often function as homo- or hetero-dimers. The goal of our project is to study the behaviors of hER-alpha ligand binding domain (LBD) when it interacts with a ligand and a coactivator peptide. From the crystal structures of a recombinant human ER-alpha LBD bound to the endogenous estrogen, 17-beta-estradiol (E2), a selective estrogen receptor modulator (SERM), raloxifene (RAL), a non-steroidal estrogen, diethylstilbestol (DES), and an antagonist, 4-hydroxytamoxifen (OHT), we have learned significant differences in the conformations of the LBD. While the conformations of LBD bound to E2, RAL or DES were very similar, the OHT complex has major structural changes around as well as distant from the ligand binding site. However, the mechanisms of actions of agonists and antagonists are complex and not well understood. In order to study the conformational effects by binding of an agonist or an antagonist in solution, we are focusing on the following: 1) application of a solution NMR technique to investigate the dynamic nature of the protein; 2) application of molecular modeling to compare the stability of the drug/protein complexes.